“The research in cellular therapies for the treatment of patients with aggressive B-cell lymphomas is one of the most active areas in hematologic malignancies,” Brooks said in an interview with OncLive®.
In the interview, Brooks discussed the effects of CAR T-cell therapy on LBCL management as a whole, the superior efficacy of axi-cel vs historical standard-of-care (SOC) therapies for patients with relapsed/refractory LBCL, how axi-cel use in the second-line setting complicates decision-making surrounding optimal strategies for subsequent-line therapies in patients who experience disease relapse, and ongoing research that may position CAR T-cell therapy earlier in the treatment sequence.
Brooks is an associate staff physician in the Department of Hematology and Oncology at the Cleveland Clinic Taussig Cancer Institute in Ohio, as well as a member of the Population and Cancer Prevention Program at Case Comprehensive Cancer Center.
OncLive: What autologous CAR T-cell therapies are currently approved by the FDA for the treatment of patients with hematologic malignancies?
Brooks: Autologous, CD19-targeted CAR T cells are an established SOC therapy for patients with relapsed/refractory hematologic malignancies, including LBCL. There are 3 currently available CAR T-cell products that are used to treat these patients: axi-cel, tisagenlecleucel [tisa-cel; Kymriah], and lisocabtagene maraleucel [liso-cel; Breyanzi]. Initial data from phase 2 trials in the third- or later-line settings came forth to indicate effective and durable responses that were long lasting in approximately 40% of patients [who received these products].
What were the key findings of the phase 1/2 ZUMA-1 (NCT02348216)trial of axi-cel in refractory LBCL?
The ZUMA-1 trial was the first [phase 2 trial] to demonstrate [the efficacy of] axi-cel [in patients with refractory LBCL]. Approximately 100 patients received this CAR T-cell product, having an overall response rate of [82%] and a complete response [CR] rate of [54%].1 Long-term follow-up of this study indicated that [31%] of patients had a sustained CR that lasted for an average of 5 years.2
How did the phase 3 ZUMA-7 trial (NCT03391466)findings build on the ZUMA-1 data?
With the demonstrable efficacy of [CAR T-cell] products in later-line settings, it was natural to try to investigate their efficacy in earlier lines of therapy. The ZUMA-7 trial explored whether axi-cel could demonstrate superiority compared with SOC salvage platinum-containing chemoimmunotherapy followed by high-dose therapy and autologous hematopoietic progenitor cell transplantation in a prospective, randomized head-to-head trial. In this study, patients with LBCL with primary refractory disease—those who did not achieve a CR to frontline therapy or those with early relapse of aggressive B-cell lymphoma within 12 months of completion of first-line treatment—were randomly assigned to receive either axi-cel or 2 to 3 cycles of platinum-containing salvage chemotherapy.3 If this group of patients responded, they would move on to receive high-dose therapy and transplant. These 2 populations—primary refractory patients and those with early relapse—have been demonstrated to be the highest-risk group of patients and those who have the worst outcomes when they are found to have these phenotypes of their disease. More modern, novel therapies with different mechanisms of action are necessary.
In ZUMA-7, 65% of patients receiving axi-cel [n = 180] achieved a CR vs only 32% of those receiving the SOC therapy [n = 179]. The 24-month event-free survival [EFS] rate was 41% in the axi-cel group vs only 16% in the SOC group. The median overall survival [OS] in a later publication with longer follow-up was not reached vs only [31.1] months in patients receiving chemotherapy and transplant.4
Most patients in the SOC group received subsequent off-protocol cellular immunotherapy. In spite of this prespecified sensitivity, analyses that adjusted for this crossover continued to suggest improved OS with the initial approach of axi-cel treatment. With these data and this support of the superiority of EFS with axi-cel compared with standard chemotherapy followed by stem cell transplant, in April 2022, axi-cel was FDA approved for the treatment of patients with primary refractory or early relapsed LBCL.
Following the ZUMA-7 findings, what are the next steps for improving treatment outcomes for patients with relapsed/refractory LBCL?
One of the potential consequences of axi-cel in the second-line setting is that it is not going to be clear what is the best strategy for subsequent-line therapy for patients who ultimately relapse. Fortunately, a relatively new class of medications called bispecific antibodies has emerged as an option for patients in this setting, and it is one of the most active areas of research in aggressive B-cell lymphomas. These medicines, although they have modest single-agent activity both [in clinical trials] and in real-world studies, are increasingly being used in combination with a multitude of different agents—targeted therapies, antibody-drug conjugates, and conventional cytotoxic chemotherapy—to improve the outcomes of patients who would otherwise have a poor overall prognosis.
What might the future look like regarding the investigation of axi-cel in B-cell lymphomas?
One of the most highly anticipated studies currently ongoing is the phase 3 ZUMA-23 trial [NCT05605899], where patients with high-risk LBCL are being enrolled and randomly assigned in a prospective fashion to a SOC therapy vs axi-cel. [This trial is investigating] the use of CAR T-cell therapies in the first-line setting for patients who are at high risk of having [inferior treatment] outcomes. The findings of that study are highly anticipated because they will revolutionize the treatment paradigm and beg the question of whether CAR T-cell therapy can and should be applied for all patients, even those who have never been treated before.
References
- Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447
- Neelapu SS, Jacobson CA, Ghobadi A, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. 2023;141(19):2307-2315. doi:10.1182/blood.2022018893
- Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
- Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665
